The present invention relates generally to anti-inflammatory drugs and more particularly to novel compounds for inhibition of the cyclooxygenase activity of prostaglandin synthase, an essential enzyme in the prostaglandin synthesis pathway. Prostaglandins (PGs), leukotrienes (LTs), histamine, bradykinin, platelet-activating factor (PAF) and interleukin-1 have been implicated in inflammation reactions in tissues (Vane and Botting, 1987). With the exception of nonnucleated erythrocytes, all cells are capable of synthesizing PGs from arachidonic acid (as diagramed schematically in FIG. 1 by Smith, et at., 1991). PGs are released in response to many kinds of trauma or any disturbance of the cell membrane. The pathological release of PGs contributes to inflammation, fever and pain.
It will be appreciated by those skilled in the art that development of nonsteroidal anti-inflammatory drugs has focused primarily on inhibitors of cyclooxygenase activity of prostaglandin endoperoxide synthase. To this end, there have been numerous attempts to synthesize inhibitors of PGH synthase. Some well-known inhibitors are aspirin and other aspirin-like NSAIDs, including aryl acetic acids (among them indomethacin and its analogs), Etodolac (Humber, 1987) and anthranilic acids. The anti-inflammatory action of aspirin depends on the inhibition of PGE.sub.2 synthesis by salicylate (Higgs, et at, 1987).
The mechanism of inactivation of cyclooxygenase activity of PGHS by the non-steroidal anti-inflammatory drug aspirin is well known (Vane, 1971). Aspirin inactivates the cyclooxygenase activity of holo PGHS by regioselective acylation of Ser 530 in sheep (Ser 529 in humans), which then blocks the entry of AA into the substrate binding site. Site-directed mutation of Ser 530 to Ala 530 maintains normal enzymatic activity suggesting that Ser 530 is not responsible for cyclooxygenase catalysis (Dewitt et at., 1990). It was thought that Ser 530 possessed the most reactive OH group in PGHS owing to an heme induced conformational change that placed electron rich residues with Ser 530, however subsequent studies with other acetylating agents such as N-acetylimidazole did not result in regioselective acetylation (Wells et al., 1992; Wells et al., 1993). These results suggested the importance of the carboxylic acid moiety in aspirin which could hydrogen bind in the vicinity of Ser 530 leading to covalent modification of Ser 530.
Attempts to construct a working model for the active site of fatty acid cyclooxygenase with the pattern recognition of known inhibitors as well as conformational minimizations of the natural substrate AA have been made. The Squibb group recently described a novel series of 7-oxabicycloheptylprostanoic acid derivatives that inhibit AA-induced platelet aggregation and AA oxygenation by platelet and bovine seminal microsomes (Pal, et at., 1992).
There are two isozymes of PGHS (PGHS-1 and PGHS-2) which share about 62% sequence identity with each other. They catalyze the first committed step of prostaglandin synthesis: the conversion of arachidonate to prostaglandin H.sub.2 (PGH.sub.2). A recent study indicates that these two isozymes are differentially sensitive to inhibition by common NSAIDs (Meade et at., 1993).
Among the attempts to invent effective nonsteroidal anti-inflammatory drugs are the disclosures for a wide variety of NSAIDs. U.S. Pat. No. 5,234,937 reveals 3,5-di-tertiary-butyl-4-hydroxyphenyl oxazolyl methanones and related compounds which act as antiinflammatory agents. The related U.S. Pat. No. 5,234,939 covers 3,5-tertiary-butyl-4-hydroxyphenyl imidasolyl methanones and related compounds which function as antiinflammatory agents. A series of U.S. Pat. Nos. 4,981,865, 5,075,330, and 5,112,846 by Belliotti et al protect N-hydroxyamide, N-hydroxythioamide, hydroxyurea, and N-hydroxythiourea derivatives of selected NSAIDs which act as antiinflammatory agents. Numerous other patents protect a wide variety of NSAIDs. The scientific literature reveals a plethora of NSAIDs, also. NSAIDs can be characterized into five groups:
(1) the propionic acid derivatives; PA1 (2) the acetic acid derivatives; PA1 (3) the fenamic acid derivatives; PA1 (4) the biphenylcarboxylic acid derivatives; and PA1 (5) the oxicams
or a pharmaceutically acceptable salt thereof. However, of these NSAIDs in use today, only aspirin is known to bind covalently with its target enzyme which results in an irreversible interaction. In contrast, the majority of NSAIDs bind competitively with their target enzymes giving rise to a reversible interaction between the NSAID and its target enzyme.
What is needed, then, is a compound which acts as a potent NSAID and covalently binds to the active site on the PGHS enzyme. This compound is presently lacking in the prior art.